Anaesthetic compositions



,May 21, 1957 A, E. w. sMxTH ET AL 2,793,155

'ANAESTHETIC coMPosI'rIoNs Filed Feb.' 24, 195e United States Patent OANAESTHETIC COMPOSITIONS Arthur Ernest Wilder Smith, Geneva, and EmilHofstetter, Wolhusen, Switzerland, assignors to Ed. Geistlich Sohne A.G. fur Chemische Industrie, Wolhusen, Switzerland, a corporation ofSwitzerland Application February 24, 1956, Serial No. 567,580

6 Claims. (Cl. 167-52) This invention relates to improved anaestheticcompositions of particular use in local anaesthesia.

In copending application Serial No. 555,305 tiled December 27, 1955 ofEmil Hofstetter there are described certain new compounds of the generalformula also described certain new compounds having the general formula1 y Rx y R-Nny-cofcHr-J-RI RI I 1I (where R is-a monochlorophenylradical or a dichlorophenyl radical which dichlorophenyl: radical has atleastY one chloro-substituent in the metaor para-position, R1 ishydrogen or an alkyl group having from one to ve carbonv atoms, R2 is analkyl group having from one to five carbon atoms and R3 is adialkylamino group containing from two to four carbon atoms or apiperidyl or monoalkyl piperidyl group), which have local anaestheticactivity.

We have now found that an anaesthetic composition having unexpectedlyadvantageous properties is obtained by mixing together the compound ofthe Formula I above in which X represents a phenyl radical, that is-diethylamino butyric acid-anilide, or its non-toxic wateroralcohol-soluble salts with the compound of Formula II above in which Ris an o,pdichlorophenyl radical, R1 is hydrogen, R2 is methyl and R3 ispiperidyl, that is -piperidylbutyric acid-(o,pdich1oro)-anilide or itsnon-toxic wateror alcohol-soluble salts.

According to the invention, therefore, we provide a local anaestheticcomposition comprising a sterile injecable solution of a mixture of amember of the group consisting of -diethylamino butyric acid-anilide andnontoxic waterand alcohol-soluble salts thereof and a member of thegroup consisting of -piperidyl butyric acid- (o,pdichloro)anilide andnon-toxic waterand alcoholsoluble salts thereof.

By the `term non-toxic as applied to the salts of the two compoundsmentioned above is meant such salts as are not substantially more toxicunder normal conditions of administration than the compounds themselves.Such non-toxic salts specilically include the citrates, tartrates,acetates, sulphates and particularly the hydrochlorides of thesecompounds.

The local anaesthetic compositions provided according to the inventionhave important and unexpected advan- 2,793,155 :Ratented May 2l, 1957'ice tages over either of the component compounds comprising thecomposition; Thus, a local anaesthetic should have ideally inter alia,the following properties.

(1) It should have a short latent period; that is the period between theinjection of the anaesthetic and the time when it takes etect should beas short as possible.

(2) The level of anaesthesia induced should be deep and should bemaintained for a suliicient period.

(3) There should be no substantial irritation of lthe tissue oninjection, and no substantial ill-etects on the patient. j

Now, it was found that although -diethylamino butyric acid-anilide is agood anaesthetic in many respects it has a long latent period; alsoanaesthesiav is not maintained for as long a period as might in somecases be desirable. The compound -piperidyl butyric acid-(o,p-dichloro)anilide also has a long latent period, and whilst it is long acting itgives n'se to some tissue irritation in concenhations of greater thanabout 0.5%.

The anaesthetic compositions of the present invention have theunexpected property of a very short latent period, which is considerablyless than that of either -diethyl-v amino butyric acid-anilide or-piperidyl butyric-(op dichloro)anilide. The duration of anaesthesia isalso long and a considerable depth of anaesthesia is maintained. l

We have found it particularly advantageous to use a composition in theform of a'sterile injectable solution' containing a mixture of fromabout 1.5 to 4.0%, preferably 2.0%, of -diethylamino butyricacid-anilideor itsl;

, non-toxic water or alcohol-soluble salts with from about;

0.2 to 0.5%, preferably 0.4%, of -piperidyl butyric acid-v(o,pdichloro)-anilide or its non-toxicwateror'alcohol-` soluble saltsthe percentages being expressed asa weight' by volume onthe-metri'c'sallbased o rithe'volumeof'the. injectable solutions. 'j'Afpiefe'rred infin-*toxic 'salt is 7 the hydrochloride'. When usedinthese proportions the irritant properties of l ipiperidyl butyric acid'A("oipdiiV chloro)v-anilide` 'are'.'not noticeable onv injection of the'composition." "'NVA '.1 f1' The anaestheticcompositions according to'the inven-' tion are" particularly applicable to'dental' surgery orvsur? gery of a minor nature, although they are also applicableV asganglionic blocking agents in major surgical intervention. In the caseof dental surgery they are conveniently made up in the form of dosageunits adapted for parenteral administration each unit convenientlycornprising 1 to 3 ccs. of the anaesthetic composition of our invention.l

According to a feature of the invention we provide alocal anaestheticcomposition in dosage unit form adapted for parenteral administration indental surgery each dosage unit comprising fronil to 3 ccs. of a sterileinjectable solution comprising a mixture of about-2`.0% of a member ofthe group consisting of -diethylamino butyric acidanilide and non-toxicwater, and alcohol-soluble *salts-y thereof and about 014%' vof'amember'of'tlie group consisting of -'piperidyl butyric acid(o,pdichloro)-anilide and non-toxic waterand alcohol-soluble saltsthereof.

In the case of minor surgery such a dosage unit can conveniently be ofthe order of 1 to 5 ccs. of the composition having the concentrationabove-stated.

In the case of -rnajor surgical intervention the composition accordingto the invention finds application as a ganglionic blocking agent whichmay be parenterally administered as and where necessary, provided thatnot more than ccs, of a solution of the above-mentioned concentration isused.

The compositions according to the invention may be made up in anyconvenient liquid medium which is suitable for injection. Where thecomponents of the cornposition are in the form of their water-solublesalts for example as hydro'chlorid'es, then they' are preferably made upin the form of an aqueous solution. The injectable compositionsaccording to the invention may advantageously contain a vaso-constrictorsuch as adrenaline.`

In order clearly to demonstrate the unexpectedly short latent periodpossessed, extensive experiments have been carried out to compare thelatent period of the local anaesthetic compositions of our inventionwith that of -diethylamino butyric acid-anilide and )S-piperidyl butyricaeid-(o,pdiehoro)-anilide In the experiments carried out the personsbeing studied were injected with a particular anasthetic in aqueoussol'ution the solutions in all cases containing 1`5'-20 y ofadrenalin-noradrenalin per ce of solution. The latent period for eachanaesthetic solution' was then detenmined, this period being the timeelapsing between the moment of injection and the onset of fullanaesthesia; the experiments were carried out in all cases on the gumsofV the patients.

The results of these experiments are set' out in the aecompanyingdrawing which showsthe results in graphical form. Each curve on thegraph representsthe results obtained for a particular solution-thecomposition ofthe various solutions used being as follows:

' Percentage of. Percentage of. -diethylamino -piperidyl Solution andCurve No. butyricacid butyric acid anilide hydro- (o, pdichloro)chloride anilide hydrochloride' 2. u o. 4l 4. 0. 3 2.0 0.3 2. 0 0. 2 1.5 0. 5 2. 0 0. 5

The results obtained were the averages obtained on treat-- ing a numberof people, the number of people treatedY with solution l being 1,100;with solution. 2,. 30; withsolution 3, 50; with solution 4, 40; and withsolution 6, 300. In the case of solution 5, people were treated of whom%v complained of tissue irritation, whilst in the case of solution 7insuicient anaesthesia was produced in the 5 people who were treated.

It will be noted from the above results that the latent period for thecompositions of our invention, that is those represented by curves -5 isconsiderably less than that of -diethylamino butyric acid-anilide alone(curve 6) or of Iifi-piperidyl butyric acid (o,p-dichloro)anilide (curve7) even though this is used at so high a concentration that a certainamount of' tissue irritation results.

The latent period for Xylocaine lies between that of solutions1-4.whilst that of Procaine has a similar latent periodto that ofsolution 6.

Whilst only the use of the hydrochlonides of -diethylamino butyric acidanilide and -piperidyl butyric acid (o,pdichloro) -anilide has beenexemplified it will be appreciated. by those skilled in the art thatother salts can be used, for example,.the citrates, tartrates, acetatesor sulphates of these compounds. It will also be appreciated' thatwhilst'only wafer has been exemplili'ed as the injectable medium anyother convenient compatible medium may be used. Thus, for example, themedium used may contain alcohol in which case alcohol-soluble salts ofthe compounds comprising the composition may conveniently be used.

It is thusseen: that' the new'local anaesthletic compositions ofourinvention possess certain unexpected advantages.A In particular theyhave azshort" latent and give a long period of deep anaesthesia.'

l. A local anaesthetic composition comprising a sterile injectablesolution: of afmxtureV of a'- mernber of' the group consisting, of[.t-diethylamintv butyric acid-anilide and non-toxic waterandalcohol-soluble salts thereof and a member of the group consisting of-piperidyl butyric acid(o,pdichloro)anilide and non-toxic waterandalcoholsolnble salts thereof.

2. A localV anaesthetie composition' comprising a sterile injectablesolutionof a mixture of from about 1.5 to 4.0% of: a' member ofjthegroup consisting of -diethylamino butyric acid-:militie4v andlnon-toxic' waterand alcoholsoluble salts thereof and of' from' about 0.2to 0.5% of a member of the group consisting of -piperidyl butyricacid-(o,pdichloro)ani1ide and non-toxic waterand alcohol-soluble saltsthereof 3. A local' anesthetic-composition comprising a sterile- 'iinjectableA solution of amixture of about' 2.0% of the hydrochlorideofTv -ded1ylamino butyrie acid anilidef andi v adapted forparentfnfalliadministration: in dental' surgery each dosage unitcomprising from l to 3 ecs, of a-sterile injectable solution comprisinga mixture of about 2.0% of a member of the group consisting of-diethylamino butyn'c acid-anilideandiinon-toxic waterand alcoholsolublesalts thereof and about 0.4% of a member of the groupconsisting of-piperidyl. butyric acid-(o,p-dich1oro). anilide. anchl non-toxic.waterand alcohol-soluble salts thereof.

5. A local anaesthetic composition' indosage unit form adaptedfor'parent'eral administration in dental surgery eachdosage unitcomprising from l' to 3 ccs. of an aqueous solution comprising a mixtureof about 2.0% of the hydrochloride of -diethylamino butyric aoid-anilideand about 0.4% of the hydrochloride of -piperidyl butyricacid-(o,p-dichloro)anilide.

6. A- localanaesthetic composition 'in dosage unit form adapted forparenteral administration in minor surgery each-dosage: unit comprising.from. 1 to 5 ccs, of a sterile injectable solution comprising a mixtureof about 2.0% of a memberl of the group consisting. of -diethylaminobutyric acid-anilide and` non-toxic waterand alcohol solution saltsthereof and about 0.4% of a member of the group consisting of -piperidylbutyric acid-{0,p-dichloro)anilide and non-toxic water andalcohol-soluble salts thereof.

No, references cited.

1. A LOCAL ANAESTHETIC COMPOSITION COMPRISING A STERILE INJECTABLESOLUTION OF A MIXTURE OF A MEMBER OF THE GROUP CONSISTING OFB-DIETHYLAMINO BUTYRIC ACID-ANILIDE AND NON-TOXIC WATER- ANDALCOHOL-SOLUBLE SALTS THEREOF